COMPOSITION COMPRISING SULCRALFATE AND AN ANTIMICROBIAL AGENT/ION-EXCHANGE RESIN COMPLEX

Abstract: Pharmaceutical compositions for use in the treatment of gastrointestinal disorders associated with Helicobacter pylori infection comprising a bioadhesive agent and a drug/ion-exchange complex.

Description: COMPOSITION COMPRISING SULCRALFATE AND AN ANTIMICROBIAL AGENT/ION- EXCHANGE RESIN COMPLEX This invention relates to the treatment of gastrointestinal disorders and pharmaceutical compositions for use therein. More particularly the invention relates to pharmaceutical compositions containing an antimicrobial agent active against Helicobacter pylori and their use in the treatment of gastrointestinal disorders associated with Helicobacter pylori infection. Helicobacter pylori (formerly known as Campylobacter pyloridis) is a spiral-shaped Gram-negative organism which resides beneath the mucus layer of the stomach. Many recent studies have shown an association between the presence of H. pylori in the gastric mucosa and histologically confirmed gastritis. In the light of these results, it has been suggested that the organism may be a pathogen which causes, or at least exacerbates, gastritis, and may also be important in the aetiology of peptic ulceration. Reviews on the state of the art include those by CAM. McNulty in J. Infection, 1986, 13, 107-113, and by CS. Goodwin et al. in J. Clin. Pathol., 1986, 39, 353-365. H.pylori is known to be susceptible to a large number of antimicrobial agents in vitro. It has been shown that treatment of gastritis with antimicrobial agents, for example β-lactam antibiotics such as amoxycillin, or bismuth salts, leads to eradication of the associated H.pylori organisms in vivo. GB 2 243 549 A (Reckitt & Colman) claims the use of the non-antibiotic antimicrobial agent triclosan for the preparation of a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori infection. For comparative purposes, GB 2 243 549 A discloses the in vitro testing of 11 antimicrobial compounds in addition to triclosan versus Helicobacter pylori. based on methods described by McNulty et al. (Antimicrobial Agents & Chemotherapy, 28, 837- 838, 1985). MIC results for triclosan, tinidazole, cetalkonium chloride, cetyl pyridinium chloride, clioquinol, hexetidine, dichlorophen, halquinol, 4-hexyl recorcinol, hibitane (chlorhexidine gluconate), PCMX (chorloxylenol), and guaiacol are disclosed. International Patent Application Publication No. WO 92/18111 (SmithKline Beecham) discloses a range of antimicrobial agents, including cationic antimicrobial agents, benzene derivatives, phenols, amines and certain naturally occuring substances as having useful activity against Helicobacter pylori. Materials which prolong the residence time of drugs within the stomach have received considerable attention as platforms for controlled drug delivery. Bulking agents have utility as retention enhancers through retardation of stomach emptying. Gastric sustained release compositions are also obtained by formulation of medicaments so as to produce a floating raft within the stomach. Alginate substances are particularly suitable for the production of floating alginate rafts. Bioadhesive agents constitute a further example; they are able to prolong residence time by adhesion to mucus membranes and thus ensure an optimal contact with the absorbing surface. Many different types of bioadhesive materials, both natural and synthetic, can be used in the design of controlled drug delivery systems. GB 2 243 549 A discloses a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori comprising triclosan which may be formulated as a gastric sustained release composition having prolonged residence time within the stomach and continuously releasing triclosan during that time. Triclosan compositions formulated so as to produce floating alginate rafts within the stomach, or as muco-adherent coated granules or spheroids, are identified as suitable sustained release compositions. Sucralfate is a basic aluminium sulphate sucrose complex having ulcer healing and buffering properties. Sucralfate has been shown to act by forming a bioadhesive gel structure under aqueous acid conditions which is believed to provide a local protective barrier. The preparation and use of sucralfate is described in for example US Patent No. 3, 432, 489 and "The Merck Index" 11th Edition (1989), page 1400, Entry No. 8853. EP-A-0 403 048 (Warner-Lambert) describes medicated compositions comprising sucralfate and a therapeutically effective amount of a medicament which is a) substantially water insoluble, or b) a mixture of a water-soluble medicament and a release-delaying material which on admixture forms a substantially water-insoluble medicament. Antibacterials are listed as one of several types of therapeutic agent where the medicament is an antiulcer medicament. WO 92/18111 also discloses compositions in which the antimicrobial agent active against Helicobacter pylori is coformulated with one or more substances providing a sustained release and/or prolonged retention time of the antimicrobial agent in the stomach. Sucralfate is identified as one such substance. The use of ion-exchange resins to mask the unpleasant taste of drug substances is well known. The use of drug/ion-exchange resin complexes in controlled release drug delivery systems is also known. The slow release of drugs from ion-exchange resins was recognised in 1950 (J. Chem. Soc, 2915-9, 1950) as a potential mechanism for a sustained-release dosage form. US 2,900,332 discloses drug-resin complexes prepared by interaction of cationic ion-exchange resins with basic drugs such as amphetamine and codeine. When a drug-resin complex of this type is orally administered, drug release is initiated when the acidic environment of the gastro¬ intestinal tract is encountered. Later developments include film-coated resinates providing an additional diffusion barrier to prolong drug release (DE 2 246 037 & GB 1 544 761). WO 92/11871 (Allergan Inc.) describes a stable suspension for controlled delivery of a pharmaceutical compound comprising drug loaded ion-exchange resin particles incorporated in an erodible polymeric matrix to form microparticulates. When suspended in a fluid medium the encapsulating matrix shields the drug loaded ion- exchange resin from solvent interaction. When administered to a target site, typically characterised by rapid fluid turnover or drainage, erosion of the polymer matrix and release of the pharmaceutical compound is initiated. It has been found that the controlled drug release and retentive properties of a composition comprising sucralfate and a water-soluble antimicrobial agent effective against Helicobacter pylori are impaired due to poor entrapment of the drug in the bioadhesive sucralfate gel matrix formed when the composition is contacted with the acidic environment of the stomach. It has now been found that this problem is overcome by complexing the water- soluble drug with an ion-exchange resin prior to combination with sucralfate. The insoluble complex is able to precipitate with the sucralfate gel matrix formed in the acidic environment of the stomach. Such a complex has the added benefit of masking bitter tasting drugs and further prolonging the residence time of the drug in the vicinity of the target bacteria within the stomach by controlling drug release from the ion- exchange resin in the presence of ionic species. Accordingly, the present invention provides a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water- soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin. A composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin for use in therapy also forms part of the present invention. The invention also extends to the use of a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water- soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin for the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter pylori infection. Suitable water-soluble antimicrobial agents for use in compositions of the present invention include cetyl pyridinium chloride (CPC), water-soluble forms of chlorhexidine, in particular chlorhexidine hydrochloride, bismuth compounds such as bismuth aluminate, bismuth carbonate, bismuth subcitrate, bismuth subgalate and bismuth subsalicylate, and miconazole. A wide range of cationic ion-exchange resins is potentially available to form drug-resin complexes for use in the present invention. Suitable pharmaceutically acceptable cationic ion-exchange resins are commercially available and include a range of synthetic cationic ion-exchange resins with different polymeric matrices which may be cross-linked. A synthetic cationic ion-exchange resin may for example be a polymer of styrene, or acrylic or methacrylic acid, and the resin may derive its exchange activity from either weakly or strongly acidic groups such as carboxylic acid or sulphonic acid groups. Ion-exchange resins particularly suitable for use in compositions of the invention include strongly cationic resins having sulphonic acid groups on a polystryene polymer matrix, which resins are suitably cross-linked, preferably by a divinyl or polyvinyl compound such as divinylbenzene. The proportion of cross-linking may vary from 1 to 20%, suitably from 1 to 12%, and preferably from 7 to 9% by weight cross-linking. Suitable resins are those commercially available under the trade names Amberlite and Duolite from Rohm and Haas Co. and Dowex from the Dow Chemical Co.. The resin may be in either acid form or in the form of a salt with an alkali metal such as sodium or potassium. Where the water-soluble antimicrobial agent is a pharmaceuticaly acceptable acid addition salt, the chosen resin will be in its salt form. Alternatively, where the water-soluble antimicrobial agent is presented as a free base, the resin will be in its acid form. Examples of drug-resin complexes for use in the present invention are those formed between CPC or chlorhexidine HC1 and the sodium form of a sulphonated styrene-divinylbenzene resin, for example Amberlite IRP-69, or the potassium form of a methacrylic acid-divinylbenzene resin, for example Amberlite LRP-88. A further example is that formed between miconazole and a methacrylic acid-divinybenzene resin in the free acid form, for example Amberlite IRP-64. The scope of invention is not limited to any particular ratio of the antimicrobial agent to ion-exchange resin. It has however been found that optimal absorption and release of antimicrobial agent is achieved when the antimicrobial agent content of the drug-resin complex is up to 10% by weight, suitably between 0.001% and 10% by weight and preferably between 0.001% and 2% by weight. The particle size of the ion-exchange resin influences not only the difiiision rate of the antimicrobial agent from the drug-resin complex but also the retention time of the resinate 7er se in the stomach. A number of commercially available ion-exchange resins have particle size distributions which favour prolonged gastric residence times and, unless otherwise indicated by the requirements of particular formulation types, these are preferred. Drug preparations based on ion-exchange complexes wherein the resinate particle size is greater than about 120μm are known to impart a gritty texture which renders them unpalatable if formulated as liquid suspensions or as chewable tablets. Accordingly, for these formulation types, resinates containing a significant proportion of particle sizes above 120μm are contra-indicated, in order to provide a product for oral consumption having good mouth feel. Formulation types such as swallow- tablets, lozenges or pills are not however constrained with respect to particle size for reasons of mouth feel. It is however generally preferred to use a resinate with a maximum particle size no greater than 120μm and particularly preferred to use a resinate with a maximum particle size no greater than 65 μm. Adsorption of antimicrobial agent onto the ion-exchange resin may be carried out by standard procedures well known in the art, for example as described in US 2,990,332. Thus, for example, a commercially available ion-exchange resin may be added directly to a solution of the antimicrobial agent in an appropriate solvent. Pre¬ conditioning of ion-exchange resins prior to complex formation may be desirable in order to remove any potentially toxic extractibles and/or to facilitate easier processing and analysis of the resulting resinate. The dose level of the antimicrobial agent may be selected according to the potency of the drug on a weight basis. A suitable dosage level for CPC ranges from about 0.01 mg to aboutl mg per dosage form, typically from about 0.05 mg to about 0.2 mg. Where the antimicrobial agent is chlorhexidine, it may be present in an amount from about 0.01 mg to about 0.3mg per dosage form, typically from about 0.05mg to about 0.2 mg. For miconazole, a suitable dosage range is about 0.01 mg to about 0.3 mg per dosage form, typically from about 0.02 mg to about 0.1 mg. Sucralfate is suitably present in an amount from about 100 mg to 1000 mg per dosage form, typically from about 300 mg to 800 mg, for example 500 mg. Compositions for use in the present invention may also contain one or more pharmaceutically acceptable carriers or excipients. Compositions may be formulated for oral administration in solid or liquid form, for example as tablets, capsules, lozenges, granules, powders, suspensions or dispersions. Granules and powders may be ingested directly, or alternatively dispersed in water or other suitable vehicles prior to administration. Capsules may be of the hard or soft gelatin type, including chewable soft gelatin capsules. Compositions may be formulated using conventional carriers or excipients and well established techniques. Compositions may for example contain preservatives, buffering agents, suspending agents, flavourings, bulking agents, binders, adhesives, lubricants, disintegrants, colouring agents, sweeteners, adsorbents, thickeners and diluents appropriate to their form. Accordingly, the present invention includes a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water- soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin, further comprising a pharmaceutically acceptable carrier. The invention also provides a method of treatment of gastric disorders associated with Helicobacter pylori infection comprising administering to a sufferer an effective amount of a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble drug having activity against Helicobacter pylori and a cationic ion-exchange resin. In a further aspect, the invention provides a pharmaceutical composition for use in the treatment of gastric disorders which comprises sucralfate and a drug/ion- exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin. The following Examples illustrate the invention but are not limiting with respect thereto. Example 1 illustrates tablet dosage forms. Tablet formulations may be swallowed for dispersal in the stomach, chewed in the mouth or dispersed in water before consumption. The Example describes the quantity (in mg) of the representative components in a single dosage form. The antimicrobial agent and ion-exchange resin are combined in the conventional manner to produce a drug/ion-exchange resinate. The resinate and sucralfate are blended along with conventional ingredients as appropriate, such as tabletting aids, fillers and palatability aids and the blend is tabletted on a conventional machine. Example 1 - Tablet Formulations Formulation No. 1 2 3 4 5 6 Sucralfate 500 500 500 500 500 500 CPC 0.05-0.2 0.05-0.2 - - - - Chlorhexidine HC1 - - 0.05-0.2 0.05-0.2 - - Miconazole - - - - 0.02-0.1 0.02-0.1 Ion-exchange resin 10 50 10 50 10 50 Starch 100 100 100 100 100 100 Icing sugar 250 250 250 250 250 250 Flavour 2 2 2 2 2 2 Povidone 10 10 10 10 10 10 Magnesium stearate 20 20 20 20 20 20 Example 2 Preparation of CPC/ Ion-Exchange Resinate lOg of ion-exchange resin (Amberlite IRP69), milled to a maximum particle size of 63μm, was suspended in 43ml of distilled water, to which 43ml of 0.002mg/ml CPC was added. The mixture was agitated for thirty minutes at room temperature. The suspension was spun down in a benchtop centrifuge for ten minutes at 400rpm, and the supernatant was removed. The pellet was resuspended with distilled water and filtered through a GF/B filter. The resinate was dried in an oven at 60°C Example 3 Preparation of Resinate-Sucralfate Mixture lg of sucralfate (ex. Katsura) was mixed with 0.0.2g of CPC resinate (as prepared in Example 2) in a beaker. The powder mixture was added to 24ml of 0.08M HC1 / 0.034M NaCl solution and stirred until a paste formed between the two components of the mixture. An adhesive paste was formed within twenty seconds of addition to the acidic cation solution.

Claims: Claims 1. A pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin. 2. A composition as claimed in claim 1 wherein the antimicrobial agent is cetyl pyridinium chloride, a water soluble form of chlorhexidine, a bismuth compound or miconazole. 3. A composition as claimed in claim 1 or 2 wherein the cationic ion-exchange resin is a cross-linked polymer of styrene or methacrylic acid. 4. A composition as claimed in any one of claims 1 to 3 wherein the antimicrobial agent content of the drug-resin complex is between 0.001 and 10% by weight. 5. A composition as claimed in any one of claims 1 to 4 wherein the maximum particle size of the drug/ion-exchange complex is 120μm. 6. A pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin, and a pharmaceutically acceptable carrier. 7. A pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin for use in therapy. 8. Use of a pharmaceutical composition comprising sucralfate and a drug/ion- exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin for the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter pylori infection. 9. A method of treatment of gastric disorders associated with Helicobacter pylori infection comprising administering to a sufferer an effective amount of a pharmaceutical composition comprising sucralfate and a drug/ion-exchange complex formed between a water-soluble antimicrobial agent having activity against Helicobacter pylori and a cationic ion-exchange resin.

Inventors: O'MULLANE JOHN EDWARD, POILE STEVEN, O'MULLANE, JOHN, EDWARD, POILE, STEVEN
Applicants: MULLANE JOHN EDWARD O, POILE STEVEN, SMITHKLINE BEECHAM PLC, O'MULLANE, JOHN, EDWARD, POILE, STEVEN
Application year: 1994
Main classification: A61K33
IPC codes: A61K31, A61K33, A61K45, A61K47, A61P1, A61P31